This is a Phase I, open-label, single-arm, dose-escalation and expansion study designed to evaluate the safety, tolerability, and preliminary antitumor activity of dual-targeting VEGFR1/PD-L1 chimeric antigen receptor (CAR) T-cells in patients with solid tumors presenting with pleural, peritoneal, or leptomeningeal metastases. Despite advances in systemic therapies, patients with serosal cavity and leptomeningeal dissemination face extremely poor prognoses and limited treatment options due to the unique immunosuppressive tumor microenvironment and the physical barrier of these anatomical sites. Preclinical evidence suggests that simultaneous blockade of VEGFR1-mediated angiogenesis and PD-L1-mediated immune checkpoint signaling via a bispecific CAR-T construct may synergistically overcome local immunosuppression and enhance tumor eradication in these sanctuary sites. The study consists of two phases: a dose-escalation phase utilizing a standard 3+3 design and backfilling design to determine the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of locoregionally administered CAR-T cells, followed by a dose-expansion phase to further assess safety and preliminary efficacy at the RP2D. Eligible patients will receive a single infusion of VEGFR1/PD-L1 dual-CAR T-cells via intrapleural, intraperitoneal, or intrathecal routes, depending on the primary site of metastasis. The primary endpoints are the incidence of dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs) graded by CTCAE v5.0. Secondary endpoints include objective response rate (ORR) , progression-free survival (PFS), overall survival (OS), and assessment of CAR-T cell persistence and cytokine profiles in peripheral blood and local effusion fluids.
The study comprises two independent cohorts based on metastatic site and route of administration: Cohort 1 - Pleural or Peritoneal Metastases (Intracavitary Administration): This cohort enrolls patients with solid tumors who have developed pleural or peritoneal metastases and have failed standard-of-care therapies. A standard 3+3 dose-escalation design is applied with three dose levels: 2×10⁶, 5.0×10⁶, and 1.0×10⁷ CAR-T cells/kg. Cells are administered via intrapleural or intraperitoneal injection based on the predominant metastatic site. Cohort 2 - Leptomeningeal Metastases (Intrathecal Administration): This cohort enrolls patients with cytologically or radiologically confirmed leptomeningeal metastases from solid tumors who have failed prior standard therapies. A dose-escalation with backfill cohort strategy is employed, with three prespecified dose levels (DL): DL1 at 7.5×10⁶ CAR-T cells, DL2 at 1.5×10⁷ CAR-T cells, and DL3 at 3.0×10⁷ CAR-T cells, all administered via intrathecal injection. The escalation method differs by dose level: DL1 follows an accelerated titration design (single participant), while DL2 and DL3 follow the standard 3+3 design. Backfill cohorts will be initiated only after the DL2 main cohort has completed the DLT observation period and the DL3 main cohort has enrolled 3 participants who have entered the DLT window. Thereafter, newly enrolled patients will be randomly allocated (for dose assignment only) to either the DL2 or DL3 backfill cohorts, with 3 additional participants per level. The final recommended phase II dose (RP2D) for leptomeningeal metastases will be comprehensively determined using pooled safety and tolerability data from both the main escalation and backfill cohorts. The dose-limiting toxicity (DLT) observation period is 21 days post-first infusion for both cohorts. Adverse events are graded per NCI-CTCAE v5.0. Following RP2D determination for each cohort, a dose-expansion phase will be initiated to further evaluate safety and preliminary efficacy in a larger patient population.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
40
Autologous T cells genetically engineered to express a chimeric antigen receptor targeting both VEGFR1 and PD-L1. Cells are administered via locoregional routes.
West China Hospital, Sichuan University
Chengdu, Sichuan, China
RECRUITINGAEs and SAEs
Safety
Time frame: 6 months after infusion
Dose-limiting toxicity (DLT)
Tolerability evaluation
Time frame: 21 days
Recommended phase II dose (RP2D).
Efficacy dose
Time frame: Approximately 2 years.
Objective Remission Rate (ORR).
Time frame: From date of first CAR-T cell infusion until the date of first documented disease progression or death,up to 5 years.
Progression-Free Survival (PFS ).
Time frame: From date of first CAR-T cell infusion until the date of first documented disease progression or death,assessed up to 5 years.
Duration Of Control Rate (DCR).
Time frame: From date of first CAR-T cell infusion until the date of first documented disease progression or death,assessed up to 5 years.
Duration Of Response (DOR).
Time frame: From date of first CAR-T cell infusion until the date of first documented disease progression or death,assessed up to 5 years.
Overall-Survival (OS).
Time frame: From date of CAR-T cell infusion until date of death from any cause, assessed up to 5 years
CSF Tumor Cell Clearance Rate
Proportion of participants with conversion from positive to negative CSF cytology/flow cytometry
Time frame: Up to 5 years
Duration of CSF Clearance
Time from first CSF clearance to CSF re-positivity or death
Time frame: Up to 5 years
Neurological Symptom and Intracranial Pressure Improvement Rate
Composite of ≥1-grade neurological symptom improvement and ≥20% reduction in CSF opening pressure from baseline, assessed concurrently
Time frame: Up to 5 years
CAR-T cell numbers.
PK/PD
Time frame: 24 months.
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